Vitamin A and synthetic analogs (retinoids) can modulate the growth and differentiation of normal, premalignant, and malignant cells in-vivo and in- vitro. Squamous metaplasia that develops during vitamin A deficiency resembles the premalignancy caused by chemical carcinogens. Some retinoids can inhibit and reverse carcinogen-induced preneoplastic lesions in spithelial organ cultures and can suppress carcinoma development in carcinogen-treated animals. Compelling evidence exists that tobacco-induced squamous cell carcinoma of the lung develops gradually in sequential histologic changes that begin with potentially reversible squamous metaplasia/dysplasia and progress to carcinoma-in-situ and finally to invasive carcinoma. Several non-randomized pilot studies with a small number of patients have shown that certain retinoids have some benefit in the treatment of bronchial metaplasia/dysplasia. We believe that these studies should be corroborated and conducted in the form of a randomized double-blind controlled study. Our group is well qualified to pursue such a study because of our successful previous experience and our ongoing NCI chemoprevention trial in dysplastic oral leukoplakia. This study will combine a clinical trial and basic studies to establish a rationale for the use of retinoids as chemopreventive agents in bronchial squamous metaplasia/dysplasia. The clinical trial, a randomized double-blind study, will compare the effectiveness of 13-CRA and placebo using histologic criteria. To complement histologic assessment, measurable or evaluable biochemical and biopsies as intermediate endpoints. The basic studies will examine the effects of 13-CRA for genomic alteration markers (micronuclei and cellular DNA), markers of squamous cell differentiation (transglutaminase, involucrin, and keratins), as well as markers of abnormal growth regulation (epidermal growth factor receptors, polymerase alpha and Ki 67). The results of the basic studies will be compared to the results of the clinical trial and any correlation analyzed. This study will provide the information necessary to develop a rational approach for premalignant squamous metaplasia/dysplasia and to direct the future development of chemoprevention in lung cancer.